The purpose of this project is to elucidate the neural mechanisms and principles of treatment of chronic pain syndromes, with particular attention to the drug treatment of pain caused by nerve injury. There is growing evidence from animal studies that neuropathic pain may be largely mediated by CNS excitation at glutamate receptors. Our previous work showed that the NMDA receptor antagonist ketamine reduces neuropathic pain but has severe side effects including impairment of cognition, movement, and mood. Based on the hypothesis that low affinity NMDA channel blockers, which bind to the ion channel for only a fraction of a second, will cause less impairment of normal CNS function, we have carried out two clinical trials of dextromethorphan in patients with diabetic neuropathy pain and post-herpetic neuralgia. Both studies showed that dextromethorphan reduces diabetic but not post-herpetic pain. These are the first clinical trials to show that chronic treatment with NMDA antagonists is reasonably well tolerated and relieves pain. Animal studies suggest that another class of glutamate receptors--AMPA/kainate receptors--play a key role in pain perception and neural sensitization. We carried out the first human studies of any AMPA/kainate antagonist in 26 normal volunteers. Dose-limiting side effects were transient visual obscurations described as "white fog", presumably caused by blockade of AMPA/kainate receptors in the visual system. The antagonist, LY293558, reduced pain and hyperalgesia caused by prior injection of intradermal capsaicin by about 50% at doses producing no side effects, but had no effect on perception of thermal and electrical pain stimuli applied to normal skin. These results suggest that AMPA/kainate antagonists may have utility as analgesics in conditions that include a component of sensitization of central neurons.